Ocular inflammatory disease (OID) is a general term embracing a number of diseases and conditions in which inflammation affects the eye or surrounding tissues. The diagnostic name given to an OID is typically based on the location of the ocular inflammation. For example, uveitis is inflammation in the uveal tract; scleritis is inflammation of the sclera, pars planitis is inflammation of the pars plana, and so forth. OIDs cause pain, irritation, and watering, and may result in loss of visual function. For example, uveitis is the third leading cause of blindness in the developed world. OIDs can be caused by infections, malignancy, exposure to toxins, response to surgery or injury, and autoimmune disorders.
A number of autoimmune diseases exist in which the eye or various parts of the eye becomes a target for an immune-mediated inflammatory attack. Patients with an autoimmune-mediated OID (AOID) often exhibit cellular and humoral responses to retinal antigens such as retinal arrestin (retinal soluble antigen, S—Ag), interphotoreceptor retinoid binding protein (IRB), and antigens related to melanin and its metabolism, including GP100, MART1, TRP1 and TRP2 (Pennesi, G. et al. (2003) J. Clin. Invest. 111:1171-1180; Gocho, K. et al. (2001) Invest. Ophthalmol. Vis. Sci. 42:2004-2009; Sugita S. et al., (1996) Int. Immunol. 8:799-803; Yamake, K. et al. (2000) J. Immunol. 165:7323-7329. However, in many cases of AOID, the target antigen(s) are not known.
Often, OID is a manifestation of a systemic autoimmune disease, and the eye is one of a variety of organs throughout the body that are being attacked. Examples of such systemic autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, polyarteritis nodosa, relapsing polychondritis, Wegener's granulomatosis, sclerodemia, Behcet's disease, Reiter's disease, inflammatory bowel disease (ulcerative colitis and Crohn's disease) and ankylosing spondylitis. However, the eye may be the specific and only target affected in autoimmune diseases such as ocular cicatricial pemphigoid, Mooren's corneal ulcer, and various forms of uveitis.
AOIDs such as uveitis have been treated by various classes of compounds including steroids and nonsteroidal anti-inflammatory agents such as dexamethasone, fluorometholone, prednisolone, indomethacin, aspirin, flubiprofen and diclofenac. However, a number of uveitis cases are not responsive to or become refractory to these drugs (see, e.g., Kulkarni, P. (2001) Journal of Ocular Pharmacology And Therapeutics 17:181-187). Also, these drugs are associated with serious side effects such as cataracts, glaucoma, delayed wound healing, altered prostaglandin production, corneal complications, increased ocular pressure, superinfections, and reduced immunity to infection (see, e.g., Id., at 181; Guidera, A. C., et al. (2001) Ophthalmology 108:936-944; Olsen, E. G. & Davanger M. (1984) Acta Ophtalmol. 62:893-899).
Because the existing therapies for AOID have less than optimal efficacy or undesirable side effects, new treatment regimens are needed. It has been suggested that it may be clinically beneficial to modulate the immunoregulatory mechanisms involved in the pathogenesis of AOID (Caspi, R. R. (2002) Int Rev Immunol 21:197-208).
These pathogenic mechanisms have been investigated using experimental autoimmune uveitis (EAU), which is an animal model of human autoimmune uveitis. EAU is induced in experimental animals such as mouse, rat, guinea pig, rabbit, and monkey by immunization with a retinal antigen shown to be reactive in uveitis patients (e.g., arrestin, IRBP, rhodopsin/opsin, phosducin, recoverin) or by infusion of T cells specific for these antigens. Studies using the EAU model provided apparently contradictory evidence about the mechanisms for induction and progression of this disease. The results of some experiments indicated that the main pathogenic pathway in EAU was due to the role of interleukin-12 (IL-12) in promoting the generation of IFN-γ producing Th1 effector cells (Caspi, R. R. (2002) Int Rev Immunol 21:197-208; Tarrant, T. K. et al., (1998) J. Immunol. 161:122-127; Caspi, R. R. (1998) Clin Immunol Immunopathol 88:4-13; Xu, H. et al. (1997) Cell Immunol 178:69-78. However other experiments showed that IFN-γ deficient knock-out mice were susceptible for EAU, that EAU is exacerbated by neutralization of endogenous IFN-γ, and that elevated levels of IFN-γ were protective against EAU in wild-type mice (Caspi, R. R. et al. (1994) J. Immunol. 152:890-899; Jones et al., J. Immunol. 158:5997-6005; Tarrant, T. K., et al. (1999) J. Exp. Med 189:219-230.
Thus, prior to the present invention, it was not clear which immune pathways should be targeted in developing therapies for preventing or treating autoimmune ocular inflammatory disease.